Method and apparatus for guiding ablative therapy of abnormal biological electrical excitation

ABSTRACT

This invention involves method and apparatus for guiding ablative therapy of abnormal biological electrical excitation. In particular, it is designed for treatment of cardiac arrhythmias. In the method of this invention electrical signals are acquired from passive electrodes, and an inverse dipole method is used to identify the site of origin of an arrhythmia. The location of the tip of the ablation catheter is similarly localized from signals acquired from the passive electrodes while electrical energy is delivered to the tip of the catheter. The catheter tip is then guided to the site of origin of the arrhythmia, and ablative radio frequency energy is delivered to its tip to ablate the site.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation in part of U.S. application Ser. No.09/413,969 filed Oct. 7, 1999 now U.S. Pat. No. 6,308,093.

GOVERNMENT SUPPORT

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as provided for by the terms of Grant No.NAG5-4989 awarded by the National Aeronautics and Space Administration.

BACKGROUND OF THE INVENTION

The electrical activity generated in certain organs in the human body isintimately related to their function. Abnormalities in cardiac and brainelectrical conduction processes are principal causes of morbidity andmortality in the developed world. Appropriate treatment of disordersarising from such abnormalities frequently requires a determination oftheir location. Such localization of the site of origin of an abnormalelectrical excitation is typically achieved by painstaking mapping ofthe electrical activity on the inner surface of the heart or the brainfrom electrodes or a catheter. Often, this recording must be done whilethe abnormal biological electrical excitation is ongoing.

Radio frequency catheter ablation procedures have evolved in recentyears to become an established treatment for patients with a variety ofsupraventricular [Lee, 1991; Langberg, 1993] and ventricular arrhythmias[Stevenson, 1997; Stevenson, 1998]. However, in contrast tosupraventricular tachycardia ablation, which is highly successfulbecause the atrio-ventricular node anatomy is known, ventriculartachycardia ablation remains difficult because the site of origin of thearrhythmia could be anywhere in the ventricles.

Sustained ventricular tachycardia is often a difficult arrhythmia tomanage. One of the most common indications for radio frequency catheterablation of ventricular tachycardia is arrhythmia refractory to drugtherapy that results in frequent discharges from an implantablecardioverter-defibrillator. Radio frequency ablation is also indicatedwhen the ventricular tachycardia (VT) is too slow to be detected by theimplantable cardioverter-defibrillator or is incessant [Strickberger,1997].

Selection of the appropriate target sites for ablation is usually basedon a combination of anatomical and electrical criteria. The ability ofthe physician to deliver radio frequency energy through a catheter atthe reentry site is restricted by the limitations of the currenttechnology that is employed to guide the catheter to the appropriateablation site. The principal limitation of the radio frequency ablationtechnique is the determination of the correct site for delivery of theradio frequency energy. Conventionally, this determination is achievedby painstaking mapping of the electrical activity on the inner surfaceof the heart from electrodes on the catheter. Often, this recording mustbe done while the arrhythmia is ongoing. This is a major problem,especially for those arrhythmias which compromise hemodynamic functionof the patient. Many arrhythmias for this reason are not presentlyamenable to radio frequency ablation treatment.

The acute lesion created by radio frequency current consists of acentral zone of coagulation necrosis surrounded by a zone of hemorrhageand inflammation. Arrhythmias may recur if the target tissue is in theborder zone of a lesion instead of in the central area of necrosis. Ifthe inflammation resolves without residual necrosis, arrhythmias mayrecur several days to several weeks after an apparently successfulablation [Langberg, 1992]. Conversely, an arrhythmia site of origin thatwas not initially successfully ablated may later become permanentlynonfunctional if it lies within the border zone of a lesion and ifmicrovascular injury and inflammation within this zone result inprogressive necrosis [Nath, 1994]. Thus, the efficacy and long termoutcome of catheter ablation depend on accurate determination of thesite of origin of the arrhythmia.

Catheter ablation of sustained monomorphic ventricular tachycardia lateafter myocardial infarction has been challenging. These arrhythmiasarise from reentry circuits that can be large and complex, with broadpaths and narrow isthmuses, and that may traverse subendocardial,intramural, and epicardial regions of the myocardium [deBakker, 1991;Kaltenbrunner, 1991].

Mapping and ablation are further complicated by the frequent presence ofmultiple reentry circuits, giving rise to several morphologicallydifferent VTs [Wilbur, 1987; Waspel, 1985]. In some cases, differentreentry circuits form in the same abnormal region. In other cases,reentry circuits form at disparate sites in the infarct area. Thepresence of multiple morphologies of inducible or spontaneous VT hasbeen associated with antiarrhythmic drug inefficacy [Mitrani, 1993] andfailure of surgical ablation [Miller, 1984].

Several investigators have reported series of studies of patientsselected for having one predominant morphology of VT (“clinical VT”) whowere treated with radio frequency catheter ablation [Morady, 1993; Kim,1994]. It is likely that this group of patients represents less than 10%of the total population of patients with VT [Kim, 1994]. The patientmust remain hemodynamically stable while the arrhythmia is induced andmaintained during mapping. The mapping procedure may take many hoursduring which the arrhythmia must be maintained. Thus, currently radiofrequency catheter ablation is generally limited to “slow” ventriculartachycardia (˜130 bpm) which is most likely to be hemodynamicallystable.

Ablation directed towards the “clinical tachycardia” that did not targetother inducible VTs successfully abolished the “clinical VT” in 71% to76% cases. However, during followup up to 31% of those patients withsuccessful ablation of the “clinical VT” had arrhythmic recurrences,some of which were due to different VT morphologies from that initiallytargeted for ablation.

Furthermore, there are several difficulties in selecting a dominant,“clinical VT” for ablation. Often it is not possible to determine whichVT is in fact the one that has occurred spontaneously. In most cases,only a limited recording of one or a few ECG leads may be available. Inpatients with implantable defibrillators VT is typically terminated bythe device before an ECG is obtained. Even if one VT is identified aspredominant, other VTs that are inducible may subsequently occurspontaneously. An alternative approach is not to consider the number ofVT morphologies in determining eligibility for catheter ablation butrather to attempt ablation of all inducible VTs that are sufficientlytolerated to allow mapping [Stevenson, 1998b; Stevenson, 1997]. However,this approach requires that the patient be hemodynamically stable duringthe VT mapping procedure.

The use of fluoroscopy (digital bi-plane x-ray) for the guidance of theablation catheter for the delivery of the curative radio frequencyenergy is common to clinical catheter ablation strategies. However, theuse of fluoroscopy for these purposes may be problematic for thefollowing reasons: (1) It may not be possible to accurately associateintracardiac electrograms with their precise location within the heart;(2) The endocardial surface is not visible using fluoroscopy, and thetarget sites can only be approximated by their relationship with nearbystructures such as ribs and blood vessels as well as the position ofother catheters; (3) Due to the limitations of two-dimensionalfluoroscopy, navigation is frequently inexact, time consuming, andrequires multiple views to estimate the three-dimensional location ofthe catheter; (4) It may not be possible to accurately return thecatheter precisely to a previously mapped site; (5) It is desirable tominimize exposure of the patient and medical personnel to radiation; and(6) Most importantly, fluoroscopy cannot identify the site of origin ofan arrhythmia and thus cannot be used to specifically direct a catheterto that site.

Electro-anatomic mapping systems (e.g., Carto, Biosense, Marlton, N.J.)provide an electro-anatomical map of the heart. This method ofnonfluoroscopic catheter mapping is based on an activation sequence totrack and localize the tip of the mapping catheter by magneticlocalization in conjunction with electrical activity recorded by thecatheter. This approach has been used in ventricular tachyardia[Nademanee, 1998; Stevenson, 1998], atrial flutter [Shah, 1997;Nakagawa, 1998], and atrial tachycardia ablation [Natale, 1998;Kottkamp, 1997]. The ability to localize in space the tip of thecatheter while simultaneously measuring the electrical activity mayfacilitate the mapping process. However, this technique fundamentallyhas the limitation that it involves sequentially sampling endocardialsites. The mapping process is prolonged while the patients must bemaintained in VT. Also, the localization is limited to the endocardialsurface and thus sites of origin within the myocardium cannot beaccurately localized.

The basket catheter technique employs a non-contact 64-electrode basketcatheter (Endocardial Solutions Inc., St. Paul, Minn.) placed inside theheart to electrically map the heart. In the first part of this procedurehigh frequency current pulses are applied to a standard catheter used inan ablation procedure. The tip of this catheter is dragged over theendocardial surface, and a basket catheter is used to locate the tip ofthe ablation catheter and thus to trace and reconstruct the endocardialsurface of the ventricular chamber. Then the chamber geometry, the knownlocations of the basket catheter, and the non-contact potential at eachelectrode on the basket catheter are combined in solving Laplace'sequation, and electrograms on the endocardial surface are computed. Thistechnique has been used in mapping atrial and ventricular arrhythmias[Schilling, 1998; Gornick, 1999]. One of the drawbacks of thismethodology is that the ventricular geometry is not fixed but variesduring the cardiac cycle. In addition, the relative movement between theconstantly contracting heart and the electrodes affects the mapping.While the inter-electrode distances on each sidearm of the basketcatheter are fixed, the distances between the actual recording sites onthe endocardium decrease during systole. This leads to relative movementbetween the recording electrode and the tissue, significantly limitingthe accuracy of the mapping method. Also, the localization is limited tothe endocardial surface, and thus sites of origin within the myocardiumcannot be accurately localized.

What is needed is a means of efficiently directing the tip of a catheterto a site of origin of an arrhythmia in the heart (whether on theendocardial surface or within the myocardium itself), without the needto introduce additional passive electrodes into the heart, so thatenergy can be delivered through the catheter to ablate the site oforigin. It would be advantageous to be able to accomplish this taskwithout having to maintain the arrhythmia while advancing the catheterto the site of origin, so that the patient does not suffer the illeffects of the arrhythmia for a prolonged period. This consideration isparticularly important in the case of rapid arrhythmias that compromisehemodynamic function.

SUMMARY OF THE INVENTION

The present invention provides methods and apparatus for localizing anelectrical source within the body. The invention further providesmethods and apparatus for delivering ablative electrical energy in thevicinity of an electrical source within the body. The electrical sourcemay be located anywhere within the body. For example, the electricalsource may be within the heart and may be the site of origin of acardiac arrhythmia. The electrical source may be a focus of electricalactivity within the brain, such as a site involved in triggering anepileptic seizure, or may be located in other neurological tissue.

Cardiac arrhythmias are frequently treated by delivering electricalenergy to the site of origin of the arrhythmia in an effort to ablatethe site. To effectively perform this procedure, accurate localizationof both the site of origin of the arrhythmia and the energy deliverydevice (e.g., the tip of a catheter) is necessary. As used herein, theterm “localization” refers to determining either an absolute or arelative location. The present invention provides techniques foraccurately performing such localization. The minimally invasive and fastaspects of certain embodiments of the invention, as disclosed herein,are particularly important.

In preferred embodiments the methods of the present invention involveplacing passive electrodes on the body surface, placing activeelectrode(s) in and/or on the body, acquiring from the passiveelectrodes signals emanating from the electrical source, processing thesignals emanating from the electrical source to determine the relativelocation of the electrical source, delivering electrical energy to theactive electrode(s), acquiring from the passive electrodes the signalsemanating from the active electrode(s), processing the signals emanatingfrom the active electrode(s) to determine the relative location of theactive electrode(s), and positioning the active electrode(s) to localizethe electrical source. In another embodiment at least one of the passiveelectrodes is placed within the body, for example within the heart. Thepositioning step of the present invention may involve approximating therelative locations of the active electrode(s) and the electrical source.In preferred embodiments of the method the energy delivering step, thesecond acquiring step, the second processing step and the positioningstep are performed iteratively.

In a preferred embodiment the first processing step is used to determinethe relative location of the electrical source at a multiplicity of timeepochs during the cardiac cycle, and the positioning step localizes theelectrical source at one of the time epochs. At least one criterion maybe used to choose the time epoch. In a particularly preferred embodimentat least one of the processing steps involves fitting the acquiredsignals to a moving dipole model. In a particularly preferred embodimentof the invention the second processing step includes determining therelative location of a moving dipole that is approximately parallel tothe moving dipole fitted in the first processing step to signalsemanating from the electrical source. In one embodiment, suchdetermination is made using a multiplicity of active electrodes.

Another preferred embodiment of the invention involves deliveringablative energy in the vicinity of the location of an electrical sourcewithin the body by delivering ablative energy in the vicinity of thelocation of the active electrode(s). The active electrode(s) may belocated on a catheter, and the ablative energy may be delivered throughthe catheter. In a preferred embodiment the ablative energy is radiofrequency energy.

The methods of the present invention may further include displayingvarious parameters. Among the parameters of interest are the relativelocation of the electrical source and measures of the size, strength,and/or uncertainty in the relative location of the electrical source.

Other features and advantages of the invention will become apparent fromthe following description, including the drawing, and from the claims.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a flow chart of the method for localizing an electrical sourcewithin the body.

FIG. 2 is a flow chart of a procedure for fitting single equivalentmoving dipole parameters to ECG potentials.

FIG. 3 is a schematic diagram of an apparatus for localizing a site oforigin of an arrhythmia, guiding the delivery of ablative therapy, anddelivering ablative therapy to the site of origin of the arrhythmia.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention encompasses the finding that by employing a movingdipole model it is possible to accurately localize a source ofelectrical energy within the body relative to the location of an activeelectrode. If one can localize the site of origin of an arrhythmiaduring the cardiac cycle, it is possible to ablate the site throughdelivery of ablative electrical energy. The present invention providesmethods and apparatus for localizing an electrical source within thebody. The invention further provides methods and apparatus forlocalizing and ablating the site of origin of a cardiac arrhythmia.

The concept of considering the heart as a single dipole generatororiginated with Einthoven [Einthoven, 1912], and its mathematical basiswas established by Gabor and Nelson [Gabor, 1954]. Several investigators[Mirvis, 1981; Gulrajani, 1984], Tsunakawa, 1987] have studied thecardiac dipole in clinical practice and attempted to determine thedipolar nature of the ECG. The advantages of the use of the equivalentcardiac dipole are: (1) It permits quantification of source strength inbiophysical terms that are independent of volume conductor size (classicelectrocardiography), and (2) The active equivalent source can belocalized and assigned a location, something that cannot be done usingclassical electrocardiography.

For many arrhythmias, the electrical activity within the heart is highlylocalized for a portion of the cardiac cycle. During the remainder ofthe cardiac cycle the electrical activity may become more diffuse as thewaves of electrical activity spread. It is not possible to construct thethree-dimensional distribution of cardiac electrical sources from atwo-dimensional distribution of ECG signals obtained on the bodysurface. However, if it is known that a source is localized, then thislocalized source can be approximated as a single equivalent movingdipole (SEMD), for which one can compute the dipole parameters (i.e.,location and moments) by processing electrocardiographic signalsacquired from passive electrodes placed on the body surface or in thebody.

Fitting the dipole parameters to body surface ECG signals provides asolution (referred to herein as the inverse solution) for the dipolelocation (as well as for its strength and orientation). The location ofthe dipole at the time epoch when the electrical activity is confined tothe vicinity of the site of origin of an arrhythmia should coincide withthe site of origin of the arrhythmia. In contrast to standard mappingtechniques, the inverse solution can be computed from only a few beatsof the arrhythmia, thereby eliminating the need for prolongedmaintenance of the arrhythmia during the localization process. Inaddition, if one delivers low-amplitude bipolar current pulses to thetip of an ablation catheter and acquires the resulting body surfacesignals, the tip of the catheter may likewise be modeled as a singleequivalent moving dipole. Therefore, the same inverse algorithm may beemployed to localize the tip of the catheter. Using this information onecan guide the tip of the catheter to the site of origin of thearrhythmia.

The confounding factors of the SEMD method involve the fact that, asdescribed above, the method does not consider boundary conditions andinhomogeneities in tissue conductivity. Furthermore, even the exactposition of the passive acquiring electrodes in three-dimensional spacemay not be accurately determined. Thus the inverse solution obtained isdistorted. However, as long as the site of origin of the arrhythmia andthe tip of the catheter are identified using the same algorithm, thenwhen the two are brought together, both their positions will bedistorted by the same amount. In other words, when the algorithmidentifies that the site of origin of the arrhythmia and the cathetertip are at the same location, then they are at the same location. Thusthe distortion due to the above factors should not significantly affectthe accuracy by which one can make the tip of the ablation catheter andthe site of origin of the arrhythmia coincide. Therefore, although theSEMD method described herein may not establish the absolute locations ofthe site of origin of the arrhythmia and the tip of the catheter, it caneffectively identify their relative locations.

FIG. 1 shows a flowchart of the method according to the presentinvention for localizing an electrical source within the body. Themethod includes placing passive electrodes in or on the body to acquireelectrical signals. The signals from the passive electrodes areprocessed to determine the relative location of the electrical sourcewithin a given short time epoch. The processing steps are repeated formultiple sequential time epochs, and the location of the sourcecorresponding to the site of the origin of the arrhythmia is obtained.As used herein, the phrase “sequential time epochs” does not necessarilyimply immediately successive time epochs.

As further shown in FIG. 1, electrical energy is delivered from at leastone active electrode placed within or on the body, and the signalsemanating from the at least one active electrode (e.g., at the tip of acatheter) are acquired from the passive electrodes. Signals emanatingfrom the at least one active electrode are processed to determine therelative location of the at least one active electrode within a givenshort time epoch. Thereafter, the processes of delivering electricalenergy and determining the relative location of at least one activeelectrode are repeated until the active electrode is superposed to therelative location of the electrical source. In other words, in apreferred embodiment of the invention, the processes of deliveringelectrical energy to the at least one active electrode, acquiring fromthe passive electrodes the signals emanating from the at least oneactive electrode, processing the signals emanating from the at least oneactive electrode, and positioning the at least one active electrode areperformed iteratively. This repetition of steps 4 through 7 of FIG. 1may be terminated when the relative locations of the electrical sourceand the active electrode are within a predetermined distance (not shownon FIG. 1).

The present invention provides method and apparatus for guiding ablativetherapy within an organ system either from body surface electrodes orfrom internal electrodes. This technique explicitly recognizes that onecannot uniquely reconstruct from a two-dimensional array of electrodes athree-dimensional distribution of sources. The present invention modelsbio-electrical activity as a single equivalent moving dipole (SEMD),which is a valid model when the bio-electrical activity is highlylocalized. In the cardiac context, the evolution of the SEMD during thecardiac cycle provides a three-dimensional picture of cardiac electricalactivity.

The basic theory of the present invention derives from electromagnetictheory. The potential due to a dipole in an infinite homogeneous volumeconductor is given by the equation below. $\begin{matrix}{\varphi^{i} = \frac{p \cdot \left( {r^{i} - r^{\prime}} \right)}{{{r^{i} - r^{\prime}}}^{3}}} & \left( {{Eq}.\quad 1} \right)\end{matrix}$

where,

r^(i) is the three-dimensional vector representing the i_(th)observation location,

p is the three-dimensional vector representing the dipole moment, and

r′ is the three-dimensional vector representing the dipole location.

One may obtain the dipole parameters, i.e., p and r′, from potentialmeasurements through minimization of an objective function. One may usechi-square (χ²) as the objective function to obtain the dipole parameterestimates. χ²is given by equation 2 below: $\begin{matrix}{\chi^{2} = {\sum\limits_{i = 1}^{I}\quad \left( \frac{\varphi^{i} - \varphi_{m}^{i}}{\sigma^{i}} \right)^{2}}} & \left( {{Eq}.\quad 2} \right)\end{matrix}$

where

φ^(i) is the potential at the i_(th) electrode because of the specificdipole components,

φ^(i) _(m) is the measured potential at the i_(th) electrode,

σ^(i) is a noise measurement at the i_(th) electrode, and

I is the number of electrodes.

Because of the linear dependence of the potential (Eq. 1) on the dipolemoment parameters, the latter can be separated from the spatial dipoleparameters. Consequently, any optimization method may be applied to thespatial parameters only, while an analytic optimization procedure may beperformed to obtain the optimal fitting dipole moment parameters for aspecific set of dipole spatial parameters. We coin the term 3 plus 3parameter optimization for this algorithm.

Using the χ² as an objective function the optimal dipole momentcomponents (p_(x), p_(y), p_(z)) at each dipole location can be obtainedby solving the following system of equations: $\begin{matrix}\begin{matrix}{0 = \frac{\partial\chi^{2}}{\partial p_{k}}} \\{= {\sum\limits_{i = 1}^{I}\quad {\frac{\partial\chi^{2}}{\partial\phi_{m}^{i}}\frac{\partial\phi_{m}^{i}}{\partial p_{k}}}}} \\{{= {2{\sum\limits_{i = 1}^{I}\quad {{\frac{\phi^{i} - \phi_{m}^{i}}{\sigma_{i}^{2}}r_{k}^{i}} - \frac{r_{k}^{\prime}}{{{r^{i} - r^{\prime}}}^{3}}}}}},{k = 1},2,3}\end{matrix} & \left( {{Eq}.\quad 3} \right)\end{matrix}$

and after substituting Eq. 1 into Eq. 3, we obtain $\begin{matrix}{{\sum\limits_{j = 1}^{3}\quad {p_{j}\alpha_{kj}}} = \beta_{k}} & \left( {{Eq}.\quad 4} \right)\end{matrix}$

where $\begin{matrix}{\alpha_{kj} = {\sum\limits_{i = 1}^{I}\quad \frac{\left( {r_{k}^{i} - r_{k}^{\prime}} \right)\left( {r_{j}^{i} - r_{j}^{\prime}} \right)}{{{r^{i} - r^{\prime}}}^{6}}}} & \left( {{Eq}.\quad 5} \right)\end{matrix}$

and $\begin{matrix}{\beta_{k} = {\sum\limits_{i = 1}^{I}\quad \frac{\varphi^{i}\left( {r_{k}^{i} - r_{k}^{\prime}} \right)}{{{r^{i} - r^{\prime}}}^{3}}}} & \left( {{Eq}.\quad 6} \right)\end{matrix}$

Thus, the potential is now given by an equation of the formφ^(i)=φ^(i)(p(r′), r′), where p(r′) represents the optimal dipole momentat the location r′. This equation can now be solved for all dipolemoment components p_(k).

In a preferred embodiment of the invention the moving dipole modelpresented above is employed to localize a source of electrical activitywithin the body (e.g., a site of origin of a cardiac arrhythmia) and tolocalize at least one active electrode (e.g., the tip of a catheter).According to the invention, passive electrodes are used to acquire ECGpotentials from the body. Following data acquisition, each of the bodysurface ECG channels is examined to secure good data quality.Inadmissible data could occur, for example, due to (1) lack of contactof the electrodes to the skin or other body tissue, or (2) electrodefailure during the procedure.

Following confirmation that the data quality is adequate, in preferredembodiments of the invention the data is preprocessed. In a preferredembodiment, the R wave in the QRS complex is identified in each ECG beatand for each channel and subsequently the baseline of each beat isadjusted relative to an identified PR segment. Baseline correctionincludes estimation of the baseline in the isoelectric PR segment byaveraging successive samples in this time window for each lead andsubsequently subtracting this estimate before construction of the vectormagnitude. The resulting annotations and RR intervals may be displayedand graphically examined for evidence of spurious and/or undetectedevents. Then, fiducial points are determined by an adaptive QRS templatematching scheme to refine initial fiducial point estimates. For thisrefinement phase the vector magnitude waveform of the QRS complex fromstandard ECG leads (I, II, III) is calculated for each beat. This isperformed by calculating the square root of the sum of the squares ofeach of the three baseline-corrected standard leads. The average vectormagnitude QRS complex is then calculated with the use of initialfiducial point estimates. With this average as a template, the fiducialpoints corresponding to each QRS complex are shifted to maximize thecross-correlation between each beat and the template [Smith, 1988].Next, a median beat is created to represent each data segment byaligning each beat within the data segment according to the R wave, andidentifying the median value on a time epoch-by-time epoch basis withinthe beat. After estimation of the median beat for each channel, a noiseestimate will be obtained from each median beat (and channel) in apredefined noise window.

After completion of the preprocessing of the data, an algorithm to fitthe single equivalent moving dipole (SEMD) parameters to the ECGpotentials is applied for every time epoch in the cardiac cycle. In apreferred embodiment of the invention the algorithm shown in FIG. 2 isemployed. This algorithm utilizes a multiple seed value search (e.g., amaximum of ten seeds). A spatial criterion is imposed to eliminatesolutions that land outside a predefined volume (e.g., the volume of thebody). The distance, D_(r), between the location of the solutionresulting from each seed (i.e., the current location) and the locationof the best previous solution is determined. If the distance (D_(r)) isnot less than 0.1 cm and the χ² of the current solution (χ2_(cur)) isless than the χ² of the best solution obtained thus far (χ² _(best)),then the current solution becomes the new best solution. Alternatively,if D_(r)<0.1 cm then the final solution is set to whichever of eitherthe current solution or the best previous solutions has the lower χ².The algorithm is terminated when two solutions are found to be closerthan approximately 0.1 cm. Note that the two solutions need notnecessarily be successive solutions. A solution obtained for aparticular time epoch in a given cardiac cycle serves as the initialseed for the next time epoch. If, after all seeds are used, no solutionshave been found within a given time epoch that satisfy the spatialcriterion and are closer together than approximately 0.1 cm, thealgorithm outcome will be considered nonconvergent for that time epoch.

In another embodiment, an algorithm able to perform beat-to-beatanalysis (continuous analysis) across all channels can be employed inthe processing step. This algorithm has the ability to select a baselinesegment before each QRS complex for individual beat noise estimation.Since, for each time epoch, the algorithm obtains N solutions thatcorrespond to the best solutions of the same time epoch for the N beats,the selection of the solution with the smallest error in predicting thepotentials measured on the electrodes is chosen to be the best solutionfor that time epoch.

In a preferred embodiment of the present invention the 3-pointderivative and the maximum absolute value of the slope given by equation7 below will be used to identify the earliest activation in the surfaceunipolar ECG signal, to identify the time epoch during the cardiac cyclethat corresponds to the first indication of the site of the origin ofthe arrhythmia on the body surface $\begin{matrix}{\frac{{V\left( t_{i} \right)}}{t} = \frac{{V\left( t_{i + 1} \right)} - {V\left( t_{i - 1} \right)}}{2*{SI}}} & \left( {{Eq}.\quad 7} \right)\end{matrix}$

where SI is the sampling interval.

The same model and algorithm used to identify the region of localizedelectrical activity in the organism are also used to identify thelocation of the tip of the catheter. An oscillatory low amplitudeelectrical signal is applied at the catheter tip, which permits theinvention to discriminate between the catheter signal and thebio-electric signal. The signal from each electrode in the body is a sumof two components: the low frequency bio-electric signal and the highfrequency catheter tip signal. The invention preferably utilizes alow-pass filter to select that component of the signal originating frombio-electric activity and a lock-in amplifier to select that componentof the signal originating from the catheter tip signal.

The lock-in amplifier demodulates the signal from each electrode by theknown catheter tip signal. This process has two consequences: (1) Theeffects of the bio-electric signal are removed, and (2) The signal fromthe catheter tip is altered so that it can be treated as a simple directcurrent (DC) dipole in the same manner as the bio-electric signal.

In order to detect the bio-electric signal of interest in preferredembodiments of the invention, the signal from each electrode is firstlow-pass filtered to remove the high-frequency signal due to thecatheter tip. The low-pass filter cut-off frequency is adjusted so thatit will remove that component of the signal due to the catheter tipsignal, while leaving that component of the signal due to bio-electricalactivity unaltered.

The catheter signal amplitude is chosen such that it is sufficiently low(e.g., less than 10 microamperes) that it will not induce unwantedbio-electric activity, yet high enough that it can be readily detected.The catheter signal frequency is sufficiently high that it lies faroutside the bandwidth of the bio-electric signal of interest. At thesame time, the catheter signal frequency is not so high that thefrequency-dependent tissue impedance will differ significantly betweenthe catheter frequency and the bio-electric signal frequency. A typicalfrequency is approximately 5 kHz. It should be understood that numericalvalues for the catheter signal amplitude and frequency are presented forillustrative purposes and are not intended to limit the scope of theinvention.

FIG. 3 shows a preferred embodiment of the apparatus for localizing anelectrical source (e.g., the site of origin of an arrhythmia) within theheart, guiding the delivery of ablative energy, and delivering ablativeenergy to the vicinity of the electrical source. A multiplicity ofpassive electrodes are placed on the body surface of a subject (0) suchthat the heart may be viewed from the anterior, left lateral, rightlateral, and posterior chest. Each electrode position is provided by theoperator to analysis software included among the application programs ofcomputer (7).

Signals from the passive electrodes (1) are carried in a multi-leadcable (2) through an isolation amplifier (3) to an amplifier bank (4)with adjustable gain and frequency response. A lock-in amplifier (5) isused to identify signals that are generated by the signal generator,emanate from the active electrode(s), and are acquired from the passiveelectrodes. A low-pass filter (6) is used to identify signals acquiredfrom the passive electrodes that arise due to bio-electrical activitywithin the body. A computer (7) equipped with a multiplexor and ananalog to digital conversion card digitizes and processes the signalsemanating from a bio-electrical source within the body and the signalsemanating from the active electrode. As described in detail above, in apreferred embodiment of the invention the processing step utilizes asingle equivalent moving dipole (SEMD) model to localize both thebio-electrical source and the active electrode at a series of timeepochs. In a preferred embodiment of the invention computer (7) includesapplication programs containing code (i.e., routines) for performing thealgorithms and computations described above. The computer also createsan electronic representation of the signals acquired from eachelectrode, stores the signals, and displays the signals on a display(12). To inspect the signals the operator may display them off-line fromstorage at a rate slower than real time. The position, magnitude, andorientation of the SEMD attributed to cardiac electrical activity ateach time epoch are displayed in a three-dimensional view of the heart.The uncertainty in the position of the SEMD and the goodness-of-fitvalue of the estimation of the SEND parameters may also be displayed foreach time epoch.

The ablation catheter (9) with its at least one active electrode isplaced in the heart (8) of the subject. The catheter is connectedthrough a high-voltage isolation stage (10) that serves as an automaticswitch (the switch automatically turns off the signal generator circuitafter sensing the radiofrequency source) to a signal generator (11),which is controlled by the computer. The position, magnitude, andorientation of the dipole attributed to the tip of the catheter aredisplayed for each time epoch. The uncertainty in the position of thedipole attributed to the tip of the catheter and the goodness-of-fitvalue of the estimation of the dipole parameters attributed to the tipof the catheter are also displayed for each time epoch. A radiofrequency source (13) controlled by the operator is also attached to theablation catheter. After localization of the source of abnormalelectrical activity (i.e., the site of origin of the arrhythmia) andpositioning of the tip of the catheter at the source of abnormalelectrical activity as described above, the catheter is used to deliverablative radio frequency energy to the vicinity of the site of origin ofthe arrhythmia.

As discussed above, the location of the moving dipole, estimated byprocessing the electrical signals detected from the passive electrodes,is subject to distortion due to boundary effects and inhomogeneities intissue conductivity. This distortion may in turn depend on theorientation (direction in 3-dimensional space) of the dipole. If themoving dipole generated by an active electrode located on the tip of theablation catheter has a different orientation than the moving dipolegenerated by the electrical source, then when the estimated locations ofthe two moving dipoles are superposed by positioning of the activeelectrode, the actual locations of the two moving dipoles may still beoffset. In one preferred embodiment, in order to reduce this offset amultiplicity of active electrodes are placed on the tip of the ablationcatheter. Current is driven sequentially through different pairs ofthese active electrodes and resulting sets of potentials are detected onthe passive electrodes. The different sets of potentials are thencombined linearly and the location and moments of the moving dipolecorresponding to the linear combination are computed. This procedure iscontinued (e.g., by computing the location and moments of the movingdipole corresponding to different linear combinations of the potentials)until the moving dipole associated with a particular linear combinationof the different sets of potentials is approximately parallel to themoving dipole estimated for the electrical source.

In one preferred embodiment pulses are delivered through three differentpairs of active electrodes respectively, resulting in sets of potentialφ₁, φ₂, and φ₃ respectively. Dipoles with moments [P_(X1), P_(Y1),P_(Z1)], [P_(X2), P_(Y2), P_(Z2)], [P_(X3), P_(Y3), P_(Z3)] areestimated from the three respective sets of potentials measured on thepassive electrodes. The values of these moments constitute a matrix M.If the moments of the estimated dipole corresponding to the electricalsource are [P_(X)′, P_(Y)′, P_(Z)′] then a linear combination of thethree sets of potentials Φ given by

Φ=M ⁻¹φ  (Eq. 8)

where M⁻¹ is the inverse of the matrix M and φ is the column vector withelements φ₁, φ₂, and φ₃, will provide an initial linear combination ofthe three sets of potentials from which a dipole approximately parallelto the dipole estimated for the electrical source is computed. Furtheradjustments in this combination may improve the degree of parallelness.

It is recognized that modifications and variations of the presentinvention will occur to those skilled in the art, and it is intendedthat all such modifications and variations be included within the scopeof the appended claims.

What is claimed is:
 1. A method for localizing an electrical source in the body comprising: placing passive electrodes on the body; placing at least one active electrode in the body; acquiring from the passive electrodes signals emanating from the electrical source; processing the signals emanating from the electrical source to determine the relative location of the electrical source; delivering electrical energy to the at least one active electrode; acquiring from the passive electrodes the signals emanating from the at least one active electrode; processing the signals emanating from the at least one active electrode to determine the relative location of the at least one active electrode; positioning the at least one active electrode to localize the electrical source.
 2. A method for localizing an electrical source in the body comprising: placing passive electrodes on the body; placing at least one active electrode on the body; acquiring from the passive electrodes signals emanating from the electrical source; processing the signals emanating from the electrical source to determine the relative location of the electrical source; delivering electrical energy to the at least one active electrode; acquiring from the passive electrodes the signals emanating from the at least one active electrode; processing the signals emanating from the at least one active electrode to determine the relative location of the at least one active electrode; positioning the at least one active electrode to localize the electrical source.
 3. A method for localizing an electrical source in the body comprising: placing passive electrodes in the body; placing at least one active electrode on the body; acquiring from the passive electrodes signals emanating from the electrical source; processing the signals emanating from the electrical source to determine the relative location of the electrical source; delivering electrical energy to the at least one active electrode; acquiring from the passive electrodes the signals emanating from the at least one active electrode; processing the signals emanating from the at least one active electrode to determine the relative location of the at least one active electrode; positioning the at least one active electrode to localize the electrical source.
 4. A method for localizing an electrical source in the body comprising: placing passive electrodes in the body; placing at least one active electrode in the body; acquiring from the passive electrodes signals emanating from the electrical source; processing the signals emanating from the electrical source to determine the relative location of the electrical source; delivering electrical energy to the at least one active electrode; acquiring from the passive electrodes the signals emanating from the at least one active electrode; processing the signals emanating from the at least one active electrode to determine the relative location of the at least one active electrode; positioning the at least one active electrode to localize the electrical source.
 5. The method of claim 1, 2, 3, or 4 wherein the positioning step involves approximating the relative locations of the at least one active electrode and the electrical source.
 6. The method of claim 1, 2, 3, or 4 wherein the delivering step, the second acquiring step, the second processing step, and the positioning step are performed iteratively.
 7. The method of claim 1, 2, 3, or 4 wherein the electrical source is located in the heart.
 8. The method of claim 7 wherein the electrical source is the site of origin of an arrhythmia.
 9. The method of claim 7 wherein the first processing step is used to determine the relative location of the electrical source at a multiplicity of time epochs during the cardiac cycle.
 10. The method of claim 9 wherein the positioning step localizes the electrical source at one of the time epochs.
 11. The method of claim 10 wherein at least one criterion is used to choose the time epoch.
 12. The method of claim 1, 2, 3, or 4 wherein at least one of the processing steps comprises fitting the acquired signals to a moving dipole model.
 13. The method of claim 1, 2, 3, or 4 wherein the first processing step further comprises fitting the signals emanating from the electrical source to a moving dipole, and the second processing step further comprises determining the relative location of a moving dipole that is approximately parallel to the moving dipole fitted in the first processing step.
 14. The method of claim 13 wherein the at least one active electrode comprises a multiplicity of active electrodes.
 15. A method for delivering ablative energy in the vicinity of the location of an electrical source comprising the method of claim 1, 2, 3, or 4 and further comprising the delivery of ablative energy in the vicinity of the location of the at least one active electrode.
 16. The method of claim 15 wherein the ablative energy is radio frequency electrical energy.
 17. The method of claim 15 wherein the at least one active electrode is located on a catheter.
 18. The method of claim 17 wherein the ablative energy is delivered through the catheter.
 19. The method of claim 1, 2, 3, or 4 wherein the electrical source is located in the brain.
 20. The method of claim 3 or claim 4 wherein at least one of the passive electrodes is placed within the heart.
 21. The method of claim 1, 2, 3, or 4 further comprising the displaying of the relative location of the electrical source.
 22. The method of claim 1, 2, 3, or 4 further comprising the displaying of at least one measure selected from the group consisting of a measure of the size of an electrical source, a measure of the strength of an electric source, and a measure of the uncertainty in the relative location of the electric source.
 23. A method for localizing an electrical source in the body comprising: placing passive electrodes on the body; placing at least one active electrode in the body; acquiring from the passive electrodes signals emanating from the electrical source; processing the signals emanating from the electrical source to determine the relative location of the electrical source at a multiplicity of time epochs during the cardiac cycle, wherein the processing involves fitting the signals to a moving dipole model; delivering electrical energy to the at least one active electrode; acquiring from the passive electrodes the signals emanating from the at least one active electrode; processing the signals emanating from the at least one active electrode to determine the relative location of the at least one active electrode, wherein the processing involves fitting the signals to a moving dipole model; and positioning the at least one active electrode to localize the electrical source at one of the time epochs, wherein at least one criterion is used to choose the time epoch; and wherein the delivering step, the second acquiring step, the second processing step, and the positioning step are performed iteratively.
 24. A method for delivering ablative energy in the vicinity of the location of an electrical source comprising the method of claim 23 and further comprising the delivery of ablative energy in the vicinity of the location of the at least one active electrode, wherein the at least one active electrode is located on a catheter, wherein the ablative energy is delivered through the catheter, and wherein the electrical source is the site of origin of a cardiac arrhythmia.
 25. An apparatus for localizing an electrical source within the body comprising: at least one passive electrode adapted for placement on the body; at least one active electrode adapted for placement in the body; a signal generator for delivering electrical energy to the at least one active electrode; and a computer for processing the signals emanating from the electrical source and the at least one active electrode to determine the relative location of the electrical source and the relative location of the at least one active electrode.
 26. An apparatus for localizing an electrical source within the body comprising: at least one passive electrode adapted for placement on the body; at least one active electrode adapted for placement on the body; a signal generator for delivering electrical energy to the at least one active electrode; and a computer for processing the signals emanating from the electrical source and the at least one active electrode to determine the relative location of the electrical source and the relative location of the at least one active electrode.
 27. An apparatus for localizing an electrical source within the body comprising: at least one passive electrode adapted for placement in the body; at least one active electrode adapted for placement on the body; a signal generator for delivering electrical energy to the at least one active electrode; and a computer for processing the signals emanating from the electrical source and the at least one active electrode to determine the relative location of the electrical source and the relative location of the at least one active electrode.
 28. An apparatus for localizing an electrical source within the body comprising: at least one passive electrode adapted for placement in the body; at least one active electrode adapted for placement in the body; a signal generator for delivering electrical energy to the at least one active electrode; and a computer for processing the signals emanating from the electrical source and the at least one active electrode to determine the relative location of the electrical source and the relative location of the at least one active electrode.
 29. The apparatus of claim 25, 26, 27, or 28 wherein the electrical source is located in the heart.
 30. The apparatus of claim 29 wherein the electrical source is the site of origin of an arrhythmia.
 31. The apparatus of claim 25, 26, 27, or 28 wherein the computer fits the signals emanating from the electrical source to a moving dipole model.
 32. The apparatus of claim 25, 26, 27, or 28 wherein the computer fits the signals emanating from the at least one active electrode to a moving dipole model.
 33. The apparatus of claim 25, 26, 27, or 28 wherein the computer fits the signals acquired from the passive electrodes to a moving dipole model.
 34. An apparatus for delivering ablative energy in the vicinity of the location of an electrical source comprising the apparatus of claim 33 and further comprising: an isolation amplifier for isolating the signals acquired from the passive electrodes; and an amplifier bank for amplifying the signals acquired from the passive electrodes; a low-pass filter for identifying the signals originating from the electrical source; a lock-in amplifier for identifying the signals emanating from the at least one active electrode; a catheter, wherein the at least one active electrode is located on the catheter; a source of ablative energy for delivery in the vicinity of the at least one active electrode, wherein the ablative energy is delivered through the catheter; and a display.
 35. The apparatus of claim 25, 26, 27, or 28 further comprising an isolation amplifier for isolating the signals acquired from the passive electrodes; and an amplifier bank for amplifying the signals acquired from the passive electrodes.
 36. The apparatus of claim 25, 26, 27, or 28 further comprising a low-pass filter for identifying the signals emanating from the electrical source.
 37. The apparatus of claim 25, 26, 27, or 28 further comprising a lock-in amplifier for identifying signals emanating from the at least one active electrode.
 38. The apparatus of claim 25, 26, 27, or 28 further comprising a display.
 39. An apparatus for delivering ablative energy in the vicinity of the location of an electrical source comprising the apparatus of claim 25, 26, 27, or 28 and further comprising a source of ablative energy for delivery in the vicinity of the at least one active electrode.
 40. The apparatus of claim 39 further comprising a catheter.
 41. The apparatus of claim 40 wherein the at least one active electrode is located on the catheter.
 42. The apparatus of claim 41 wherein the ablative energy is delivered through the catheter.
 43. The apparatus of claim 39 wherein the ablative energy is radio frequency electrical energy.
 44. The apparatus of claim 25, 26, 27, or 28 wherein the electrical source is located in the brain. 